Treatment for cancer most commonly involves surgery, radiation therapy, hormone administration, and/or chemotherapy. Unfortunately, none of these therapies is highly effective against metastatic disease. Moreover, each has sufficient disadvantages such that patients often decline these therapies.
Surgical removal of malignant disease constitutes one of the most common and effective therapeutic interventions for primary treatment for cancer. Resection of all detectable malignant lesions results in no detectable return of the disease in approximately 50% of all cancer patients and may extend life expectancy or reduce morbidity for patients in whom recurrence of the cancer is seen. Not surprisingly, surgical methods for achieving more quantitative cytoreduction are now receiving greater scrutiny.
For optimal surgical resection of the cancer, it is important for the surgeon to locate the entire cancer tissue and lymph nodes, and be able to remove both the cancer and the nodes without significantly compromising adjacent structures and residual function of the organ. It is estimated that in over 40% cancer patients surgical resection still leaves the patient with some cancer cells even after resection either because the cancerous tissue could not be identified, or if identified, it was not amenable to resection. These “escaped” malignant cells lead to a significant risk of disease recurrence or even death unless they are identified and removed. In prostate cancer, the primary tumor can be treated by removal of prostate gland. However, radical prostatectomy (complete removal of the prostate) has significant drawbacks and may result in loss of urinary control and impotence.
Another therapeutic intervention involves radiation therapy either alone, or as part of a combined therapeutic regimen. However, radiation therapy can increase the risk of appearance of a second type of cancer. For example, treatment of prostate cancer using radiation therapy can increase risk of colon and bladder cancer. Treatment of invasive or metastatic cancer is often limited to palliative hormonal therapy and/or chemotherapy. While hormonal treatment induces remission of hormonally responsive cancer, the longevity of tumor remission is limited and it is not without significant toxicity, including liver damage associated with the drugs being administered, cardiovascular disease, weight gain, and osteoporosis.
Although chemotherapy may also extend lifespan, side effects of such antimitotic drugs often outweigh their benefits. Most cancer therapies today involve treatment with cytotoxic drugs that, upon administration, distribute indiscriminately to virtually all cells of the body and cause damage to both malignant and healthy cells alike. Because such conventional chemotherapies are primarily designed to kill rapidly dividing cells, they also destroy proliferating healthy cells, leading to off-target toxicities that can include myelosuppression, mucositis, alopecia, nausea/vomiting, anemia, peripheral neuropathy, and fatigue, etc. Clearly, cytotoxic therapies that can be targeted selectively to pathologic cells, avoiding collateral damage to healthy cells, would constitute a significant advance in the treatment of cancer. Therefore, there is a significant need for safer and more potent methods of treating cancer
Image-guided surgery is an emerging technique that aids surgeons to more accurately identify and remove malignant tissue without compromising the surrounding healthy tissue. One of the inherent challenges in the field of image-guided surgery is the development of imaging agents (probes) that are specific and sensitive for the cancer tissue and that selectively accumulate in the tumor to help identify the tumor. This is particularly true for occult lesions that cannot readily be identified by usual techniques. While FDA has approved indocyanine green (ICG), a non-targeted near infrared (NIR)-dye for use in image-guided surgery for certain cancers, it has been found to have significant limitations with respect to sensitivity and specificity in the identification of tumor tissue.
Motivated by a need for improved tumor identification, certain of the present inventors have previously developed a novel high affinity folate receptor (FR)-targeted NIR probe (OTL38) for use in image-guided tumor surgery for folate receptor positive cancer. OTL38 is highly stable during synthesis and storage, demonstrates ease of synthesis in small scale to GMP manufacturing, and is highly specific for FR-positive cancer cells in culture and in animal models for both primary and metastatic cancer cells, with no toxicity in rats and dogs. Based on these successful preclinical data, OTL38 entered into a Phase 1a clinical trial in Leiden, the Netherlands in January 2014 and Phase II at six different sites in USA for ovarian and lung cancer. In this study, approximately 5× more malignant lesions were removed with the aid of the OTL38 than without it. Furthermore, all the resected fluorescent lesions were confirmed by pathology to be malignant. The use of OTL38-guided resection is able to remove approximately 95% of the tumor cells. Thus, there is a need to find or improve therapies in such a way as to eliminate as much of the remaining 5% of such cancers as possible.
Part of the present invention is to identify a novel approach using a cocktail of OTL38 (folate-targeted NIR dye) and folate-targeted therapeutic agent that can be used after or during the image-guided surgery. However, one disadvantage of this approach is that both OTL38 and folate-targeted therapeutic agent will compete for same folate receptor and compound with higher affinity for the receptor will dominate the function. For example, if OTL38 has less affinity compared to folate-targeted therapeutic agent, there will be less fluorescence in the tumor and surgeon may not able to resect 5× more tumor when compared to naked eye. If on the other hand, the imaging agent is presented has a greater affinity for the receptor, then the therapeutic agent will likely be ineffective at producing the desired therapeutic outcome. Therefore, it is necessary to find the correct ratio between two compounds or adjust the pharmacokinetic properties of folate-targeted therapeutic agent to match OTL38. Alternatively, instead of adjusting pharmacokinetic properties of folate-targeted therapeutic agent to differentiate it from OTL38, the time between administration of OTL38 for image-guided surgery and administration of folate-targeted therapeutic agent for treatment can be varied. In a further alternative, a therapeutic modality that could serve the both purposes of image-guided surgery as well as a therapeutic agent would be an ideal situation.
Photodynamic therapy (PDT) is a new innovative technology that could be used both in image-guided surgery as well as in therapy. It is a treatment modality that uses a photosensitizer (PS) in combination with a particular type of light source. When the appropriate dose of PS is irradiated a photodynamic reaction occurs and generates reactive oxygen species (ROSs). These ROSs induce cell death and necrosis of diseased cells such as malignant cells, inflammatory cells, and microbial cells. PDT has been using to treat diseases ranging from cancer to age-related macular degeneration and antibiotic-resistant infections
When the photosensitizer is exposed to a specific wavelength of light, it becomes activated from a ground state (singlet state) to an excited state (triplet state) by absorbing photon (energy) from light. Then it relaxes to its ground state in three ways: through non-radiative decay, by emitting photon, and/or by transferring the energy. The detectable outcome of emitting a photon results is fluorescence. Transformation of energy causes the production of ROS that eventually lead to phototoxicity. However, the ratio between these two processes (fluorescence and phototoxicity) depends on the type of PS used. Therefore, finding the right PS with right balance is important for its use in PDT as a perfect candidate for both image-guided surgery as well as for therapy during or after surgery.
Based on the type of ROS generated, there are two types of photodynamic reaction that can occur. Type I PDT: First, the activated sensitizer can react directly with the substrate, such as the cell membrane or a molecule, and generate free radicals by abstracting an electron to form a superoxide anion radical (O2−) or transferring an electron or hydrogen atom to form a hydroxyl radical (OH*) and/or peroxide radical (OOH*). These radicals then interact with oxygen to produce oxygenated products (1O2).
In Type II PDT: the activated sensitizer can transfer its energy directly to oxygen to form singlet oxygen (1O2), which is a highly reactive oxygen species. These species oxidize various substrates.
After the PS is activated, both type I and type II PDT reactions can occur, however, the ratio between these processes depends on the type of PS used, the concentrations of substrate, amount of oxygen present within tissue, and number of PS molecules localized in the substrate or tissue.
Therefore, there is an unmet medical demand to develop innovative technologies that can selectively target PS not only to diseased cell but also to appropriate compartment within the diseased cell and to eliminate of the disease. Moreover, a PS should overcome the drawbacks that conventional non-targeted PDT agents present. For example, such a molecule should have high potency, high specificity, higher water solubility, low toxicity for healthy cells with no or minimal side effects (especially skin toxicity).
Based on the limited distribution of folate receptor (FR) in normal tissues and the higher receptor expression levels in various disease cells, folic acid (FA) remains an attractive and high affinity ligand for the selective delivery of therapeutic and imaging agents to FR+ cancer cells, activated macrophages, and tumor associate macrophages. To date, four isoforms of FR have been identified (FR-α, FR-β, FR-γ, and FR-δ), however, only FR-α and FR-β are expressed in adequate number for use in diagnostic and therapeutic applications. Over-expressed in epithelial-derived cancers, FR-α, is found in high levels in cancers such as lung, ovarian, kidney, breast, myelogenous, and brain. In contrast, FR-β is expressed on activated macrophages associated with inflammatory disease states and tumor associated macrophages, but not on quiescent or resting macrophages. Importantly, most cells accumulate their required FA (vitamin B9) via a reduced folate carrier or proton coupled folate transporter, which is unable to transport folate conjugates. Due to this selective over-expression of FR receptor on specific type cells, folate-targeted 99mTc and 111In SPECT imaging agents, 19F PET imaging agents and NIR optical imaging agents (OTL38) have been developed for the detection of FR+ cancers and inflammatory conditions in the clinic. Moreover, folate-targeted chemotherapeutic agents are also being evaluated.